Chemical modification of bases in mRNA (cmRNA) has been shown recently to significantly enhance its cellular uptake and intra-cellular stability. This strategy was shown to be safe and efficient when used for reprogramming cells, in targeted cancer therapy or for therapeutic in vivo delivery of target molecules to treat lethal lung disease or to prevent allergic asthma. This study is directed at harnessing this novel technology for regenerative applications. Specifically, this study aims to develop a biomaterial based delivery system that releases cmRNA of bone morphogenetic protein-2 (BMP-2) in a controlled fashion to induce bone regeneration. The specific aims are: (1) to synthesize and characterize a biomaterial-based cmRNA (BMP-2) delivery system and (2) to determine the in vivo efficacy of a biomaterial-based cmRNA (BMP-2) delivery system to induce bone formation. For aim 1, polyethylenimine (PEI)-cmRNA (encoding BMP-2) nanoplexes will be synthesized using established methods and characterized for size, surface charge and cmRNA condensation. The cytotoxicity and transfection efficiency of synthesized nanoplexes will be evaluated in human bone marrow stromal cells (BMSC) and murine pre-osteoblastic cells (MC3T3-E1). Expression levels of bone specific genes (osteocalcin and type I collagen), core binding factor (Cbfa)-1 and Osterix in the transfected cells will be determined. The functionality of transfection will be examined by assessing mineral nodule formation and measuring alkaline phosphatase activity in transfected cells. For aim 2, the optimized preparations will be implanted in calvarial bone defects (CBD) in Fisher 344 rats. After four and eight weeks, animals will be euthanized and new bone volume and bone area (%) at the implanted sites will be assessed using imaging and histologic techniques.